Levemir
Levemir is Novo Nordisk A/S's worldwide brand name for insulin detemir, a long-lasting insulin analog that lasts up to 24 hours in humans. Its chief benefits according to Novo are a "peakless" action, less weight gainDavid Mendosa: Benefits of Levemir than other insulins, and less day-to-day variabilityLevemir:Product Details than NPH or Lantus insulins. Levemir has been shown (by the manufacturer) to vary less day-to-day than NPH or Lantus.Variability of Levemir (detemir) studyDiagrams from Novo Nordisk showing improved day-to-day reliability over Lantus and NPH It was also found to vary less between patientsNovo--Less Variability--ADA Symposium. Veterinary use Doctors' Rand and Fleeman's protocol for Levemir use in dogs is at this linkUniversity of Queensland--Dosing information on Levemir for dogs. Levemir will need different doses in different species! A dog dose is likely to be about 1/4 of a human dose, per kg weight. The reason is revealed in the EU testing documents.EU approval testing for Levemir Levemir was found to be only 25% as effective as expected in humans, and so the concentration was quadrupled in the marketed version. But note: the 25% efficacy figure at 6nmol/unit in humans was not consistent between species, due to the albumin-binding side-chain physically interfering with insulin receptors, which vary in structure by species. Dogs and pigs found it 100% effective, but in mice and rabbits it was only 1/15 as effective per nmol. According to the tests, therefore, the marketed concentration of 24nmol/unit will seem about normal to humans but 4 times stronger than normal to dogs. Usage and Handling Levemir comes in 3ml pen cartridges, prefilled 3ml insulin pens and 10ml vials. Cartridges, when available, are compatible with all Novo Nordisk insulin pens including the Novopen JuniorNovopen Junior--Levemir Cartridges and Novopen 3 DemiNovopen 3 Demi--Levemir Cartridges, which both allow half-unit doses. Dosages finer than 1/2 unit increments must be dispensed by using a syringe with the cartridge, which is in this case quite easy. Pictorial at link belowSmall Doses From a Cartridge--Using a Syringe Pictorial Do not reinsert a cartridge into a refillable pen, or use a disposable pen mechanism, after using it with a syringe, to avoid stress on the pen mechanism and likely destruction of the cartridge or pen. Levemir's shelf life is 2 years. After first opening the product must be stored, officially for a maximum of 6 weeks, not above 30°C. It may be stored in a refrigerator (2°C - 8°C) not near a freezing compartment. Do not freeze. Protect from lightElectronic Medicines Compendium--EMC-UK. The insulin is clear and does not need rolling or agitation. Pens in use are recommended not to be refrigerated, but stored in a dark cool place below 30°C. Pen cartridges used with a syringe may of course be refrigerated for longer life. Levemir appears to work fine when stored overnight in syringes for prepared dosing. Mixing Levemir with a rapid-acting insulin analogue like insulin aspart will reduce and delay the maximum effect of the rapid-acting insulin compared to that observed following separate injections."ChildrenWithDiabetes--Mixing Levemir With Other Insulins Availability * was approved for use in Europe in 2003, * by the US FDA in June 2005. * available in Canada since January 2006, * available in the US since March 28, 2006Novo Press Release--US Availability of Levemir. FlexPens may be used with syringes just as pen cartridges may. Technical details Levemir is a clear solution created by genetically engineered yeast. It is analogous to human insulin, but includes a "fatty acyl side chain" that binds temporarily to albumin (found under the skin and in abundance in blood plasma)(98% albumin-boundInsulin Detemir) and makes the molecule "cling" to the bigger albumin molecules for a while before releasing -- making the molecules slower to enter and exit the bloodstream, and slower to enter the cells. At an ADA Symposium prior to Levemir's US approval in 2005, Novo Nordisk claimed that if NPH has a patient to patient variability of 60%, Lantus (insulin glargine) then has a 40% variability, and Levemir a 25% rate of variability. Unlike its long-acting rival Lantus, Levemir's time-delay action occurs in the bloodstream and at the target sites, not only at the subcutaneous injection site, and doesn't depend as much on the properties of the injection site or the suspension (which is Isophane, like NPH and other analog mixed insulins)The Mechanism of Protraction of Insulin Detemir Pharmaceutical Research 2004Is Insulin Detemir Able to Favor a Lower Variability in the Action of Injected Insulin in Diabetic Subjects? Diabetes & Metabolism-2005. Human insulin is altered to produce insulin detemir (Levemir) by omitting the amino acid Threonine at insulin B chain position #30 and attaching a C14 fatty acid chain to the amino acid at position #29, LysineRx List.com-Levemir. The combination of the omission of the threonine amino acid at position #30 on the B insulin chain and the addition of the fatty acid side chain at position B-#29 binds the insulin heavily to albuminUCSD Medical Center-Department of Pharmacy-Insulin Detemir-Page 2. http://www.rxlist.com/cgi/images/levemir1.gif Alterations of human insulin producing insulin detemir (Levemir) Also, the insulin now has more self association tendencies (remaining in hexamer form) than unaltered human insulin. Having the insulin stay in hexamer form longer before breaking down into dimers and monomers means slower absorption, which works out to slower onset, peak and longer duration. The mean duration of action for Levemir ranges from 5.7 hours at lower dosages to 23.2 hours at the higher ones. For doses in the range of 0.2 to 0.4 U/kg, Levemir exerts more than 50% of its maximum effect from 3-4 hours to approximately 14 hours after being administeredPeak & Duration Information. Injection sites should be rotated to avoid lipodystrophy, as with any insulinLipoatrophy can Happen With Any Subcutaneous Insulin-Endocrine Abstracts-2006. The good news is, according to Novo Nordisk, Levemir's stretched-out action in the bloodstream makes its absorption less dependent on injection site conditions (and on rotation) than Lantus. This claim is boosted by Novo's findings of lower day-to-day variability on Levemir compared to Lantus. Levemir was tested against NPH/isophane insulin for EU approval. EMEA Scientific Discussion Levemir During the tests, (see page 6) Levemir at usual insulin concentrations (6nmol per unit) was found in humans to have only about 25% of the glucose-lowering action of the same dose of NPHComparison of Levemir & NPH at Normal Insulin Concentrations, so the concentration was increased fourfold to 24 nmol/unit to compensate. The version being marketed has a concentration of 24 nmol/unit, 2400 nmol per mL. Note that this efficacy problem differs between species, see Veterinary use above. Insulin amino acid sequences Insulin Pharmacokinetics These are human activity profiles. Other animals, will differ significantly. More Information *Mechanism of Protracted Metabolic Effects of Fatty Acid Acylated Insulin, NN304 (Insulin Detemir/Levemir), in Dogs: Retention of NN304 by Albumin Diabetologia 1999 *University of Queensland--Dosing information on Levemir for dogs *Medical summary sheet *Levemir's EU approval testing details *Video: Basal/bolus method, desired vs. practical insulin action, and Levemir mechanism (Novo Nordisk) *How to Achieve a Predictable Basal Insulin? Diabetes & Metabolism 2005 *Insulin Detemir Under Steady-State Conditions: No Accumulation & Constant Metabolic Effect Over Time With Twice-Daily Use in Type 1 Diabetes Diabetic Medicine (UK)-2006 *Insulin Detemir: From Concept to Clinical Experience-Expert Opinion on Pharmacotherapy-2006 References Category:InsulinsCategory:AnalogsCategory:long-actingCategory:Novo Nordisk Category:R-DNA/GE/GMCategory:Rx StatusCategory:Intravenous use NOCategory:Meta-cresolCategory:Phenol